Similar to other encapsulated bacterial pathogens, serum anti-capsular polysaccharide antibodies confer immunity to invasive meningococcal diseases. Group A meningococcal diseases have a different epidemiological pattern than the other two major pathogenic meningococcal Groups B and C. In central Africa, Group A meningitis is endemic with a high frequency; in other parts of the world, Group A meningococci causes epidemics. In both situations, asymptomatic carriage of Group A organisms is low. In the U.S., Group A meningococcal meningitis or carriage have been virtually unknown for the past 35 years. Yet, most children and adults have protective levels of Group A meningococcal antibodies. Investigations to elucidate the origin of this "natural" immunity to Group A meningococcus revealed 11 E. coli strains of 645 stool samples from Egypt cross-reactive with meningococcal Group A. The cross-reactive antigens were the K51 and K93 capsular polysaccharides of these E. coli. Subsequently, K93 and K51 strains, identified by the antiserum agar technique, were found among isolates from patients at the Clinical Center, NIH, and in a study of stool isolates from children in Copenhagen. The K polysaccharides were isolated and their structures elucidated: K93: 3)-D-Gal-(1-4)-D-GlcUA-(1-, acetylated at 0-5 and 0-6 of the galatosyl and K51: 3)-D-GlcNac-l-PO4, acetylated at 0-6. The cross-reaction between the K93 and the Group A meningoccal polysaccharide was unexpected since they share no monosaccharide components. Immunization of rabbits with E. coli K93 or K51 strains induced bactericidal and precipitating antibodies to Group A meningococci. These K93 and K51 E. coli strains did not synthesize enterotoxins and were non-invasive in in vitro assays. Absorption studies, using pre and post immune sera from individuals injected with the Group A meningococal polysaccharide vaccine, are planned to study the origin and specificity of "natural" and immunization-induced Group A meningococcal antibodies in inhabitants of the U.S. and Africa.